There already is a strong body of evidence suggesting that long-term, consistent use of nonsteroidal anti-inflammatory agents (NSAIDs) reduces the relative risk of colon cancer. Questions recently have been raised, however, concerning the way in which these drugs exert their protective effect.
"The concepts regarding the way these drugs work have been challenged and perhaps are wrong," said Dennis Ahnen, MD, at the National Conference on Colorectal Cancer, sponsored by the American Cancer Society.
The anti-inflammatory action of NSAIDs actually may not be critical to the chemoprevention of colon cancer. Rather, NSAIDs may influence colon cancer through the induction of apoptosis, or programmed cell death, said Dr. Ahnen, associate director, Cancer Prevention and Control, University of Colorado Cancer Center, Denver.
He predicted that breakthroughs in the investigation of colon cancer chemo-prevention in the next few years will focus on the mechanism of action of NSAIDs. "We need to know the mechanism of action at both the biological and the biochemical levels so we can design better chemopreventive agents," he said.
Studies of the biologic actions of sulindac(Drug information on sulindac) suggest that the mechanism of action of NSAIDs may be more complex than previously thought, David S. Alberts, MD, said at the conference. Sulindac has properties similar to those of aspirin(Drug information on aspirin) and has been shown to reduce the number and size of polyps in individuals with familial adenomatous polyposis.
The agent is metabolized into two principal compounds, said Dr. Alberts, director, Cancer Prevention and Control, Arizona Cancer Center, Tucson. One compound is the active drug sulindac sulfide, which inhibits PGE2, a stable prostaglandin produced in the gastrointestinal mucosa. The other is sulindac sulfone, an inactive metabolite.
While sulindac sulfone decreased the number of intestinal tumors in a dose-responsive manner in an animal model, it did not inhibit PGE2, as would be expected if the drug affected the arachidonic acid pathway, Dr. Alberts said.
More recent data indicate that sulindac may operate through apoptosis. "Our research group at the Universities of Colorado and Arizona has used chromatin condensation, morphological or DNA fragmentation studies, to show that sulindac and its sulfone metabolite induce apoptosis, not necrosis, in colon tumor cells," Dr. Alberts said.
He believes that this is "very likely a common mechanism through which chemopreventive agents are working. We know this is the case with anticancer drugs at this point."